Children with severe burns manifest a catabolic state up to two years after burn. This catabolic state results in significant muscle wasting, weakness, immunosuppression, chronic bone loss, decreased growth, and concurs- rent increases in metabolic, hemodynamic, inflammatory, and scarring responses. In burned children, exercise training improves lean body mass (LBM), muscle strength, and cardiovascular endurance, though it does not restore these parameters to levels seen in healthy children. Similar improvements have been reported in burned children receiving oxandrolone, an oral synthetic testosterone analogue. In a preliminary study by the PI, the combination of exercise and oxandrolone eased burn-induced catabolism to a greater degree than ei- ther exercise or oxandrolone alone. Thus, the objective of this project is to compare the therapeutic and func- tional efficacy of the combined exercise-oxandrolone therapy with that of exercise alone, our current standard of burn care (SOC). The central hypothesis to be tested is that the combined exercise-oxandrolone therapy will be superior to exercise alone in attenuating burn-induced catabolism and increasing LBM, exercise endurance, and cardiovascular function. To this end, 100 severely burned children (7 to <21 years; burns e30% of the total body surface area) will be prospectively randomized to receive liquid oxandrolone (0.2 mg/kg/day, N=50) or placebo (N=50). Drug or placebo will be administered from hospital admission to the end of a 12-week exer- cise program (aerobic and resistive exercise), which will begin at hospital discharge. Two Specific Aims will be simultaneously pursued. Aim 1 will determine the physiological therapeutic efficacy of exercise train- ing/rehabilitation plus oxandrolone relative to that of exercise alone. The working hypothesis is that the combined therapy will be superior to exercise alone in improving LBM, muscle function, and overall cardiovas- cular function-all clinically relevant and vital functional endpoints. Aim 2 will determine the biochemical consequences of exercise training/rehabilitation plus oxandrolone relative to those of exercise alone. The working hypothesis is that the combined therapy will be superior to exercise alone in increasing protein balance, improving insulin sensitivity, and decreasing liver/tissue adiposity. This project is expected to estab- lish a new therapeutic approach that delivers more substantial improvements in the clinical and functional out- comes of burn-induced catabolism. It is also expected to provide a foundation for similar treatments in other muscle-wasting or muscle loss disorders. The long-term goal in this project is to identify clinically-effective, therapeutic interventions i the rehabilitation and recovery of severely burned children and NICHD's mission of improving rehabilitation of injured children so that they can fulfill their potential to live healthy productve lives.